The roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behavior is of great interest. Ferguson et al. selectively and transiently disrupt either one pathway or the other. They find that disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas disrupting striatonigral neurons impaired its persistence. Dorsal striatum is important for the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using viral-mediated expression of an engineered G protein–coupled receptor (hM4D), we found that activation of hM4D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM4D receptors were selectively expressed in either direct or indirect pathway neurons, CNO did not change acute locomotor responses to amphetamine, but did alter behavioral plasticity associated with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations associated with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behavior.

Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization